Association of Matrix Metalloproteinase-9 (MMP9) Variants with Primary Angle Closure and Primary Angle Closure Glaucoma

Abstract

Shorter axial length observed in patients with primary angle closure glaucoma (PACG) might be due to altered matrix metalloproteinase-9 (MMP9) activity resulting in ECM remodeling during eye growth and development. This study aimed to evaluate common variants in MMP9 for association with PACG. Six tag SNPs of MMP9 were genotyped in a Chinese sample of 1,030 cases, including 572 PACG and 458 primary angle closure (PAC), and 499 controls. None of 6 SNPs were significantly associated with overall PAC/PACG (P > 0.07) or with PAC/PACG subgroups (Pc > 0.18). Meta-analysis of two non-Chinese studies revealed significant association between rs17576 and PACG (ORs = 0.56, P < 0.0001); however, meta-analysis of our dataset with 4 Chinese datasets did not replicate this association (ORs = 1.23, P = 0.29). Prior significant association for rs3918249 in one Caucasian study (OR = 0.63, P = 0.006) was not replicated in meta-analysis of 3 Chinese studies including this study (ORs = 0.91, P = 0.13). Significant heterogeneity between non-Chinese and Chinese datasets precluded overall meta-analysis for rs17576 and rs3918249 (Q = 0.001 and 0.04 respectively). rs17577 was nominally associated with PACG in one Caucasian study (OR = 1.71, P = 0.02), but not in 3 Chinese studies including our study (ORs = 1.20, P = 0.07). Overall meta-analysis revealed nominal association for rs17577 and PAC/PACG (ORs = 1.26, Pc = 0.05). Meta-analysis did not show significant association between the other SNPs and PAC/PACG (P > 0.47). The largest association study to date did not find significant association between MMP9 and PAC/PACG in Chinese; meta-analysis with other Chinese datasets did not produce significant association. In most instances combination with non-Chinese datasets was not possible except for one variant showing nominally significant association. More work is needed to define the role of MMP9 variants in PACG.

Conflict of interest statement

Competing Interests: The authors of this manuscript have read the journal's policy and have the following competing interests: LRP has been a speaker for Allergan. LRP also served as a paid consultant to Novartis and Bausch + Lomb. LRP has received support to travel to the Think Tank Meetings by the Glaucoma Foundation in NYC and travel to the Nantucket Glaucoma Meeting by Aerie Pharmaceuticals. All other authors declare no conflict of interest or financial interest in any of the issues contained in this article. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Linkage disequilibrium plot of the 6 tag SNPs around MMP9 in the Chinese dataset of this study.

The numbers in the diamond indicate r2; black represented r2 = 1, shades of grey indicated 0< r2 <1, and white referred to r2 = 0. Chromosomal positions were based on NCBI build 36.3 (National Center for Biotechnology Information, Bethesda, MD).

Fig 2. Meta-analysis with prior studies of the association between rs17576 and PAC/PACG.

Odds ratio was calculated per each increase in minor allele A. The summary odds ratio was 0.56 (95% CI: 0.42–0.74) for the non-Chinese populations and 1.23 (95% CI: 0.83–1.82) for the Chinese populations. Significant heterogeneity between the non-Chinese and Chinese populations precluded an overall meta-analysis for rs17576 (Q = 0.001, I2 = 90%). The Bonferroni corrected significance level was set as 0.01 (0.05/5).

Fig 3. Meta-analysis with prior studies of the association between rs3918249 and PAC/PACG.

Odds ratio was calculated per each increase in minor allele T. The summary odds ratio was 0.63 (95% CI: 0.45–0.88) for the Caucasian population and 0.91 (95% CI: 0.80–1.03) for the Chinese populations. Significant heterogeneity between the Caucasian and Chinese populations precluded an overall meta-analysis for rs3918249 (Q = 0.04, I2 = 75%). The Bonferroni corrected significance level was set as 0.01 (0.05/5).

Fig 4. Meta-analysis with prior studies of the association between rs17577 and PAC/PACG.

Odds ratio was calculated per each increase in minor allele A. The summary odds ratio was 1.71 (95% CI: 1.09–2.67) for the Caucasian population, 1.20 (95% CI: 0.99–1.45) for the Chinese populations, and 1.26 (95%CI: 1.06–1.50) for the combined Caucasian + Chinese populations, respectively. The odds ratios between the Caucasian and Chinese datasets were not significantly heterogeneous (Q = 0.15, I2 = 52%). The Bonferroni corrected significance level was set as 0.01 (0.05/5).